Oncogenes encode proteins that induce cells to undergo malignant transformations. Oncogenic Ras is such a protein present in 90% of pancreatic carcinomas and 1/3 of all human cancers. Thyreos Corporation has licensed drugs that inactivate Ras by displacement from its anchorage site in the cell. These drugs inhibit Ras-dependent human tumors grown in nude mice. There are no toxic effects at doses that cause tumor regression. To register Ras antagonists with the FDA for cancer therapy is a major long-term goal of Thyreos. The specific aims of this grant will begin this process: we will establish procedures that solubilize antagonist in novel cyclodextrins so that they can be administered buccally and parenterally. The studies will select between two newly discovered cyclodextrin delivery systems. Completion of these tasks will lead to toxicology and to Phase 1 clinical trials. Currently, there are no Ras antagonists on the market and the antagonists that are been developed by other companies have very different mechanism of action from those of Thyreos. PROPOSED COMMERCIAL APPLICATIONS: The Ras antagonists are the subject of this grant will be registered with the FDA and marketed in the U.S. if they are shown to be effective by clinical trials. The attractiveness of these agents for cancer treatment is that they are without all the side effects of conventional chemotherapy. It is anticipated that these drugs could be used in up to one third of human tumors. They are likely to be particularly effective in treatment of pancreatic cancer, which is the third leading cause of cancer death in the U.S.